The Chinese Journal of Clinical Pharmacology,Part 1: Mechanism Study,Vol 33,No. 01
Objective To investigate the effects of tetramethylprazine on left ventricular hypertrophy and the regulation of nicotinamide adenine dinucleotide (NADPH) oxidases in renovascular hypertension of rat. Methods Hypertensive rats were obtained by using two-kidney two-clip (2K2C) method. Rats were classified into sham-operated group, model group, low- and high-dose experimental groups (tetramethylprazine, 30, 60 mg·kg
?1·d
?1) and control group (candesartan, 10 mg·kg
?1·d
?1). The drugs were continuously administered for 2 weeks. Left ventricular (LV) hemodynamic parameters, serum superoxide dismutase (SOD), malondialdehyde (MDA) and hydrogen peroxide (H
2O
2) levels were measured. The ratio of LV weight to body weight (LVW/BW) was calculated. Hematoxylin-eosin (HE) staining was used for morphological analysis. RT-polymerase chain reaction and Western-blot were performed to investigate the protein expressions of brain natriuretic peptide (BNP), β-myosin heavy chain (β-MHC) and NADPH oxidases (Nox2, Nox4 and P47phox). Results Compared with model group, aortic systolic pressure (AoSP), aortic diastolic pressure (AoDP), LV end-systolic pressure (LVESP), LV end-diastolic pressure (LVEDP) significantly decreased in low- and high-dose experimental groups with significantly (all
P < 0.05) while (+ dP/dt
max) and (? dP/dt
max) increased in low- and high-dose experimental groups with significantly (
P < 0.05). Compared with model group on LVW/BW (2.8 ± 0.3) mg·g
?1, LVW/BW of (1.9 ± 0.2), (1.7 ± 0.4) mg·g
?1 in low- and high-dose experimental groups significantly decreased (
P < 0.05). Compared with model group, SOD significantly increased while MDA and H
2O
2 decreased in low- and high-dose experimental groups with significantly (all
P < 0.05). The protein expressions of Nox2 in low- and high-dose experimental groups and model group were 0.82 ± 0.08, 0.57 ± 0.05, 0.30 ± 0.13; the protein expressions of Nox4 in above three groups were 1.00 ± 0.10, 0.79 ± 0.07, 1.32 ± 0.15 and the protein expressions of P47phox in above three groups were 0.88 ± 0.08, 0.65 ± 0.06, 1.23 ± 0.15, compared with model group, the protein expression significantly decreased in low, high dose experimental groups with significantly (all
P < 0.05). Conclusion Tetramethylprazine attenuated cardiac hypertrophy possibly through decreasing NADPH oxidases (Nox2, Nox4, P47phox) expressions and oxidative stress in renovascular hypertensive rats.
The Chinese Journal of Clinical Pharmacology,Part 1: Mechanism Study,Vol 34,No. 02
Objective To clarify the protective effect of polyglycosides of
Tripterygium wilfordii Hook. F. (GTW) on salt-sensitive hypertension-induced renal injury in mice.
Methods To establish the salt-sensitive hypertension model, the mice were subjected to uninephrectomy and deoxycorticosterone acetate (DOCA)-salt treatment. The mice were assigned into the control group, model group and test group. The ones in the control group were treated by uninephrectomy and intragastric administration of 0. 9% NaCl. The ones in the model group were treated with DOCA-salt and intragastric administration of 0. 9% NaCl. The ones in the test group were treated by DOCA salt and intragastric administration of 23 mg·kg
?1·d
?1 GTW. Mice in all the three groups were continuously gavaged twice a day for five weeks in total. The excretion of urinary albumin and 8-iso-prostaglandin, the creatinine clearance, the changes in renal pathology and the monocyte/macrophage infiltration were compared among the three groups.
Results After treatment, the excretion contents of urinary albumin for the test group, control group and model group were (22.49 ± 3.97), (5.70 ± 0.98) and (48.75 ± 4.49) μg·24 h
?1. The excretion contents of 8-iso-prostaglandin for the three groups were (1.84 ± 0.30), (0.42 ± 0.08) and (3.07 ± 0.47) ng·24 h
?1. The creatinine clearance rates for the three groups were (245.02 ± 27.86), (336.53 ± 25.99) and (133.76 ± 18.18) mL·24 h
?1. The glomerulosclerosis indexes for the three groups were (0.27 ± 0.06), (0.09 ± 0.04) and (0.64 ± 0.10). The tubulointerstitial injury scores for the three groups were (1.25 ± 0.29), (0.34 ± 0.16) and (3.10 ± 0.46). The renal F4/80-positive cells for the three groups were (18.84 ± 5.36), (9.80 ± 1.72) and (63.00 ± 9.13) cell·mm
?2. The parameters described above in the model group were significantly from those in the test group and the control group (all
P < 0.05).
Conclusion GTW could ameliorate renal injury induced by DOCA-salt hypertension via inhibiting monocyte/macrophage infiltration.
Chinese Pharmacological Bulletin,Part 1: Mechanism Study,Vol 32,No. 03
Aims To observe the effect of Icariin (Ica) on apoptosis of renal tubular epithelial cell in spontaneously hypertensive rats (SHRs), and to explore its possible mechanism. Methods Totally 21 male SHR of 14 weeks were randomly divided into model group, the Ica low and high dose groups (20 or 40 mg·kg
?1, ig, bid, to 26 weeks); 14-week-old male homologous Kyoto rats (WKY) were as control group, and the number of each group was 7. WKY group and model group were administered by gavage with the same volume of double distilled water. The pathological changes were observed using the HE staining and the apoptosis was detected by TUNEL method in renal tubular epithelial cells, respectively. The mRNA levels of Bok, Bax, Bcl-2 were detected by the real time RT-PCR and the protein expression of Bcl-2, Bax and Active caspase-3 was detected by Western blot method in the renal tissue. Results Compared with WKY, the renal capsule was narrow and irregular, and the glomerular mesangial matrix was increased with the cell arrangement disorder and the capillary dilation and congestion. Several glomeruli shrank and the renal tubular epithelial cell was edema with luminal stenosis in model group. The apoptosis of renal tubular epithelial cell was evident and the mRNA levels of Bok and Bax, as well as the protein expression levels of Bax and Active caspase-3 were significantly up-regulated in model group, while the mRNA level and protein expression of Bcl-2 significantly down-regulated (
P < 0.05 or
P < 0.01). Compared with model group, the renal glomerular capsule widened; the proliferation of glomerular mesangial matrix was reduced; the cell arrangement disorder and capillary dilation and renal tubular lumen stenosis were improved in Ica group. The renal tubular epithelial cell apoptosis was decreased evidently, and the mRNA levels of Bax, Bok and protein expression of Bax were significantly down-regulated in Ica group, and the mRNA level and protein expression of Bcl-2 in Ica-H group were significantly up-regulated while the protein expression of Active caspase-3 significantly down-regulated (
P < 0.05 or
P < 0.01). Conclusion Ica can inhibit the apoptosis of renal tubular epithelial cell in spontaneously hypertensive rats and its mechanism may be related to the down-regulation of Bok, Bax, and Active caspase-3, accompanied with the up-regulation of Bcl-2.
Acta Pharmaceutica Sinica,Part 1: Mechanism Study,Vol 54,No. 04
In this paper, the lipidomics was used to analyze the changes to address how
Uncaria interrupts lipid metabolism in the liver of spontaneously hypertensive rats, and to explore the mechanism of action of
Uncaria. All the experiments were approved by the animal protection and use committee of Shandong University of Traditional Chinese Medicine. UHPLC-Q Extractive orbitrap high-resolution mass spectrometry was used to collect lipid metabolite information of the rat livers. Through pattern recognition, matters with noticeable differences were recognized. Mass spectrum and data base searching helped to identify the potential biomarkers. Pattern recognition results indicated that the rats from control versus SHR group showed clear differences. Compared with the rats from the control group, there are decreases in phosphatidylcholine, phosphatidic acid, diacylglycerol and sphingomyelin in rats from the SHR group, however lysophosphatidylcholine, triglyceride, linoleic acid, arachidonic acid and ceramide are increased.
Uncaria could regulate the disorder of lipid metabolism by interfering with glycerophospholipid, sphingolipid, linoleic acid, and arachidonic acid metabolic pathways. This study provided the mechanistic understanding of the impact of
Uncaria on lipid metabolism and revealed the lipid metabolism pathways affected to offer the explanation for the complex mechanism of action.
China Journal of Chinese Materia Medica,Part 1: Mechanism Study,Vol 43,No. 05
This study aimed to investigate the antihypertensive effect and possible mechanism of
Dendrobium officinale flos on hypertensive rats induced by high-glucose and high-fat compound alcohol. The hypertensive models were successfully made by high-glucose and high-fat diet, with gradient drinking for four weeks, and then divided into model control group, valsartan (5.7 mg·kg
?1) positive control group and
D. officinale flos groups (3, 1 g·kg
?1). After six weeks of treatment, the blood pressure of rats was measured regularly. After the last administration, endothelin-1 (ET-1), thromboxane B
2 (TXB
2), prostacyclin (PGI
2) and nitric oxide (NO) were tested. Endothelial nitric oxide synthase (eNOS) expression and lesion status in thoracic aorta were detected. The vascular endothelium dependent dilation of the thoracic aorta was detected by the isolated vascular loop tension test. The results showed that
D. officinale flos could significantly reduce systolic blood pressure and mean arterial pressure in hypertensive rats, inhibit the thickening of thoracic aorta and the loss of endothelial cells, reduce plasma content of ET-1 and TXB
2, and increase the content of PGI
2 and NO. After long term administration, vascular endothelium dependent dilation of the thoracic aorta was significantly increased, and could be blocked by the eNOS inhibitor (L-NAME) and increase the expression of eNOS. Therefore,
D. officinale flos has an obvious antihypertensive effect on high-glucose and high-fat compound alcohol-induced hypertensive rats. Its mechanism may be correlated with the improvement of vascular diastolic function by protecting vascular endothelial cells, and finally resist hypertension.
China Journal of Chinese Materia Medica,Part 1: Mechanism Study,Vol 44,No. 06
Previous studies of
Dendrobium officinale on anti-hypertension effect always focused only on the blood pressure, while the crude polysaccharides of
D. officinale (DOP) have been traditionally considered as the main effective substances. This study aimed to evaluate the effect of ethanol extract from
D. officinale (DOE) on blood pressure, Glu and lipid profiles in metabolic hypertensive rats induced by comprehensive dietary factors, and elucidate the composition of effective fractions from DOE. A metabolic hypertension model of rat induced by high-sugar, high-fat diet and alcohol drinking was adopted to evaluate the effect of DOE on hypertension and other metabolic disorders. Blood pressure, Glu and lipid profiles were detected to find out the features and differences of DOE and DOP on metabolic hypertension. Furthermore, DOE was separated with three different common solvents according to the polarity. Along with blood pressure, Glu, UA and lipid profile, hemorheology, oxidative index and aortas structure changes were adopted to evaluate the comprehensive effects of the most effective fractions on metabolic hypertension. Finally, HPLC-DAD-MS was adopted to identify the components of the most effective fraction. The SBP and Glu of models were decreased significantly after administration with DOE and DOP for six weeks, while TG values in DOE groups were also reduced dramatically. The DOE was separated with ether, n-butanol respectively and named NAF, NBF and NCF. SBP, TG, Glu, UA of model rats were decreased significantly after four weeks administration with NBF. The level of MDA in serum was down-regulated, while GSH-Px and T-AOC were up-regulated obviously after 12 weeks. And the blood viscosity also obviously decreased, with less collagen deposition in aorta detected by Masson’s trichrome staining. NBF was mainly composed of phenols and flavone C-glycosides, whose aglycone was apigenin, and monosaccharide was connected to C-6 and C-8. DOE had a positive effect in alleviating hypertension and metabolic disorders in rats with metabolic hypertension. Medium polarity fraction was the effective fraction of DOE, which was mainly composed of phenols and flavone C-glycosides.
Chinese Archives of Traditional Chinese Medicine,Part 1: Mechanism Study,Vol 37,No. 07
Objective: To explore the effect of Radix Salviae Miltiorrhizae on endothelial dysfunction induced by serum from hypertensive patients with blood stasis syndrome and adenosine monophosphate activated protein kinase (AMPK) activity and to further explore the potential mechanisms underlying such effects.
Methods: The human umbilical vein endothelial cells (HUVECs) were used in this research. The blood serum of hypertensive patients with blood stasis syndrome was used to induce endothelial dysfunction and then they were treated with different concentrations of Radix Salviae Miltiorrhizae (50, and 100 μg/mL) for 24 h, respectively. Kits were used to detect the levels of nitric oxide (NO) and endothelin (ET-1). Phosphorylated and total endothelial nitric oxide synthase (eNOS), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), phosphorylated and total AMPK were detected by Western Blot assay. The expressions of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were detected by real-time PCR assay.
Results: Radix Salviae Miltiorrhizae could dose-dependently increase the amount of NO and the phosphorylation level of eNOS, while it decreased the amount of ET-1, the expressions of ICAM-1 and VCAM-1, and reduced the adhesion rate of monocytes. Furthermore, the levels of inflammatory cytokines TNF-α and IL-1β were decreased and the phosphorylation level of AMPK was increased. All data were statistically significant as compared with those of the model group (
P < 0.05).
Conclusion: Endothelial dysfunction induced by serum from hypertensive patients with blood stasis syndrome was significantly improved by Radix Salviae Miltiorrhizae and its mechanism might be related to the activation of AMPK.
China Journal of Chinese Materia Medica,Part 1: Mechanism Study,Vol 45,No. 08
To identify and verify the active ingredients from Radix Astragali on hypertension-related myocardial remodeling based on network pharmacology and heart RNA-sequencing data. The database of monomers of Radix Astragali and their intervention targets was established by using network pharmacology. The genes associated with myocardial remodeling were then screened by analyzing cardiac RNA-sequencing data. An overlap between genes related to myocardial remodeling and targets of ingredients form Radix Astragali was collected to obtain monomers with protective effect on hypertension-related myocardial remodeling. Angiotensin Ⅱ (AngⅡ)-induced mouse model with myocardial remodeling was used to validate the protective effect of active ingredients from Radix Astragali on hypertension-related myocardial remodeling. Finally, a total of 81 monomers and 1 197 targets were enrolled in our database. Mouse RNA-sequencing data showed that 983 genes were significantly up-regulated and 465 genes were down-regulated in myocardial tissue of mice with hypertension-related myocardial remodeling as compared with those in the blank group, respectively. Ninety-two genes were found via overlapping between genes related to myocardial remodeling and targets, involving 59 monomers from Radix Astragali. Further research revealed that vanillic acid (VA) could intervene in 27 genes associated with hypertension-related myocardial remodeling, ranking top 1. Meanwhile, VA could significantly inhibit AngⅡ-induced increases in ratio of heart weight to body weight, that of heart weight to tibial length, ANP and BNP mRNA levels in myocardial tissues, as well as myocardial tissue damage, cardiac fibrosis level and cardiac hypertrophy level in vivo. The network pharmacology-based screening has shown that VA has protective effects against AngⅡ-induced myocardial remodeling.
Acupuncture Research,Part 1: Mechanism Study,Vol 41,No. 09
Objective To observe the effect of electroacupuncture (EA) stimulation of "Quchi" (LI 11) on arterial blood pressure (BP), sympathetic nerve activity, barorefiex sensitivity (BRS) and expression of brain derived neurotrophic factor (BDNF) and nicotinamide adenine dinucleotide phosphate (NADPH) enzyme subunit p47phox in the rostral ventrolateral medulla (RVML) in hypertension rats.
Methods A total of 45 male SD rats were randomly divided into sham operation, artificial cerebrospinal fluid (aCSF), model, "Quchi" (LI 11), and Jianyu (LI 15) groups (
n = 9 in each group). The hypertension model was established by microinjection of AngⅡ (200 μg·kg
?
1·day
?1) into the lateral ventricle (A–C: 1.0 mm, L: 1.4 mm, H: 4.5 mm) for 2 weeks (aCSF for aCSF group). After 1 week’s AngⅡ perfusion, EA (2 Hz/15 Hz, 1 mA) was applied to bilateral "Quchi" (LI 11) or "Jianyu" (LI 15) for 20 min, once daily for two weeks. The mean arterial pressure (MAP) and heart rate (HR) were detected by using a Non-Invasive Blood Pressure System (tail cuff method). The BRS (BP-to-HR transfer function) was determined by calculating the ratio of HR fluctuation (HR:HR, between post- and pre-intravenous injection of phenylephrine)/MAP fluctuation (MAP:MAP, between post- and pre-phenylephrine injection), the urinary norepinephrine (NE) level in 24 h was assayed by ELISA. Real-time PCR and Western blot were used to detect the mRNA and protein expression of BDNF and p47phox in the RVML region tissue.
Results Following modeling, the MAP, HR and 24h-urinary NE levels and p47phox mRNA and protein expression levels in the RVML were significantly increased (
P < 0.01), and the BRS was decreased significantly (
P < 0.01). After EA intervention, the MAP, HR and 24h-urinary NE levels and p47phox mRNA and protein expression levels in the RVML were considerably lower in the LI 11 group than in the model group (
P < 0.05), while the BRS level was markedly increased in the LI 11 group compared with the model group (
P < 0.05). The expression levels of BDNF mRNA and protein in the RVLM region were obviously up-regulated in the LI 11 group compared with the model group (
P < 0.05). No significant differences were found between the LI 15 group and the model group in the MAP, HR, 24h-urinary NE, BRS, BDNF mRNA and protein and p47phox mRNA and protein expression levels (
P > 0.05).
Conclusion EA stimulation of "Quchi" (LI 11) can down-regulate arterial blood pressure, sympathetic nerve activity, and increase the baroreflex sensitivity in hypertension rats, which may be related to its effects in down-regulating p47phox mRNA and protein expression in the RVML.
Acupuncture Research,Part 1: Mechanism Study,Vol 42,No. 10
Objective To explore the potential mechanism of acupuncture stimulation of Taichong (LR3) and Neiguan (PC6) in spontaneous hypertension rats (SHR) by investigating its effects on blood pressure and contents of aspartic acid (Asp) and glutamic acid (Glu) in the rostral ventrolateral medulla (RVLM) region.
Methods A total of 75 SHR were randomized into model group, Taichong (LR3) group, Neiguan (PC6) group, LR3 + non-acupuncture point group and LR3+ PC6 group (
n = 15 rats in each group), and 15 Wistar rats of the same age were grouped into the normal control group. The filiform needles were inserted into the abovementioned acupoints and non-acupoint, twirled for a while and then retained for 30 min. The treatment was conducted once per day, 15 times in total. The rats’ tail blood pressure was examined on days 1, 3, 7 and 15 after acupuncture treatment by using a non-invasive blood pressure monitor. At the end of experiment, the contents of Asp and Glu in the RVLM were detected by high-performance liquid chromatography with UV technique.
Results On days 1, 3, 7 and 15 after the acupuncture treatment, the raised systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MBP) of PC6, LR3, LR3 + non-acupuncture point and LR3 + PC6 groups were all decreased significantly compared with the model group (
P < 0.05). On day 15, the effect of the LR3 + PC6 group was significantly superior to that of the LR3, PC6, and LR3 + non-acupuncture point groups in reducing the levels of SBP, DBP, and MBP (
P < 0.05). Compared with the normal control group, the contents of Asp and Glu in RVLM were significantly higher in the model group (
P < 0.05). After acupuncture intervention, both Asp and Glu levels in the PC6, LR3, LR3 + non-acupuncture point, and LR3 + PC6 groups were markedly lower in comparison with the model group (
P < 0.05), and those of the LR3+ PC6 group were notably lower than those in the LR3 and PC6 groups (
P < 0.05).
Conclusion Acupuncture stimulation of PC6, LR3, LR3 + non-acupuncture point and LR3 + PC6 (in particular) is effective in lowering blood pressure in spontaneous hypertension rats, which may be associated with its effects in lowering Asp and Glu contents in RVLM.
